The present invention relates to novel dihydronaphthalene compounds and processes for their preparation. The compounds of the present invention have excellent 17xcex1-hydroxylase and/or C17-20-lyase inhibiting activity, thromboxane A2 synthesis inhibiting activity, and aromatase inhibiting activity, and are thereby useful as preventive and/or therapeutic agents for various male sex hormone- and female sex hormone-dependent diseases such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis, and ovarian cancer, as well as myocardial infarction, angina pectoris, and bronchial asthma.
As to the biosyntheses of sex steroids, which express various actions in the body, it is known that C21 steroids, such as progesterone, are synthesized from cholesterol; further, male sex hormones such as androstenedione and testosterone, which are C19 steroids, are synthesized by 17xcex1-hydroxylase and/or C17-20-lyase, and using these steroids as substrates, female sex hormones such as estrone and estradiol, which are C18 steroids, are synthesized. Therefore, syntheses of male sex hormones and/or female sex hormones in the body can be suppressed by inhibiting these sex steroid synthesizing enzymes, i.e., 17xcex1-hydroxylase and/or C17-20-lyase or aromatases, which enables the prevention or treatment of diseases in which male sex hormones or female sex hormones act as exacerbating factors, such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis, and ovarian cancer.
Various findings have already shown that male sex hormone-dependent diseases such as prostate cancer and prostatomegaly can be treated by reducing male sex hormone levels in the blood. The therapeutic efficacy of reducing the level of male sex hormones by orchiectomy or adrenalectomy has been known for some times, and more recently, the efficacy of reducing the level of male sex hormones derived from gonads by the administration of an LH-RH (a pituitary hormone) agonist, has been recognized. However, the abovementioned surgical removal of organs is psychologically difficult to accept, and as well causes side effects and other disorders due to the reduction of mineral corticoids and glucocorticoids derived from the adrenal gland. Meanwhile, administration of the LH-RH agonist will inhibit syntheses of hormones derived from gonads only, but not from other organs such as adreahal gland, and even causes a temporary hormone increase known as a flare up phenomenon which is unique to agonists. On the other hand, an anti-male hormone agent to antagonize the male hormone receptor has been developed, but recently, its efficacy has been found to be diminished because of changes in the male sex hormone receptor. Against this background, a more effective male sex hormone reducing agent is desirable. In this connection, inhibition of 17xcex1-hydroxylase and/or C17-20-lyase is known to reduce the levels of male sex hormones to a high degree and can be expected to be highly effective in treating male sex hormone-related diseases such as prostate cancer, prostatomegaly, and masculinization. Furthermore, inhibition of 17xcex1-hydroxylase and/or C17-20-lyase also results in the suppression of female sex hormone syntheses.
To date, both steroid compounds and non-steroid compounds have been proposed as 17xcex1-hydroxylase/C17-20-lyase inhibitors. Examples of the non-steroid compounds include an imidazole derivative described in Japanese Patent Laid-open No. 64-85975 (1989), and a condensed tri-ring azole derivative described in Japanese Patent Application No. 07-510212 (1995). However, the efficacy of these compounds is not totally satisfactory and the development of compounds with higher activity has been desired.
As a result of intensive study in view of the abovementioned state of affairs, the present inventors found that novel dihydronaphthalene compounds have excellent 17xcex1-hydroxylase and/or C17-20-lyase inhibiting activity, thromboxane A2 synthesis inhibiting activity, and aromatase inhibiting activity. Namely, an objective of the present invention is to provide the novel dihydronaphthalene compounds and processes for producing the same.
The present invention relates to the novel dihydronaphthalene compounds and processes for producing the same. The compounds according to the present invention have excellent 17xcex1-hydroxylase and/or C17-20-lyase inhibiting activity, thromboxane A2 synthesis inhibiting activity, and aromatase inhibiting activity, and are thus useful as preventive and/or therapeutic agents for various male sex hormone- and female sex hormone-dependent diseases, such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis, and ovarian cancer, as well as myocardial infarction, angina pectoris, and bronchial asthma.
The present invention relates to novel dihydronaphthalene compounds of the following general formula (1) 
wherein R1 represents hydrogen, hydroxyl, or alkyloxy, R2 represents lower alkyl, aralkyl, or phenyl, and R3 represents alkyl, phenyl, pyridyl, or imidazolyl.
More specifically, examples of the novel dihydronaphthalene compounds according to the present invention of general formula (1) include
(1) 3-[(1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(2) 3-[(5-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(3) 3-[(6-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(4) 3-[(7-methoxy-1-methyl-3 ,4-dihydro-2-naphthalenyl)methyl]pyridine,
(5) 5-methyl-6-(3-pyridylmethyl)-7,8-dihydro-1-naphthalenol,
(6) 5-methyl-6-(3-pyridylmethyl)-7,8-dihydro-2-naphthalenol,
(7) 8-methyl-7-(3-pyridylmethyl)-5,6-dihydro-2-naphthalenol,
(8) 4-[(1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(9) 4-[(5-methoxy-1-methyl-3 ,4-dihydro-2-naphthalenyl)methyl]pyridine,
(10) 4-[(6-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(11) 4-[(7-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(12) 5-methyl-6-(4-pyridylmethyl)-7,8-dihydro-1-naphthalenol,
(13) 5-methyl-6-(4-pyridylmethyl)-7,8-dihydro-2-naphthalenol,
(14) 8-methyl-7-(4-pyridylmethyl)-5,6-dihydro-2-naphthalenol,
(15) 4-[(1-ethyl-5-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(16) 4-[(1-ethyl-6-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(17) 4-[(1-ethyl-7-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(18) 4-[(6-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(19) 4-[(5-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(20) 4-[(6-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(21) 4-[(7-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(22) 4-[(6-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine hydrochloride,
(23) 6-(4-pyridylmethyl)-7,8-dihydro-2-naphthalenol,
(24) 2-(1H-4-imidazolylmethyl)-6-methoxy-3,4-dihydronaphthalene hydrochloride,
(25) 4-[(7-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(26) 4-[(5-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(27) 4-[(1-ethyl-6-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(28) 4-[(1-ethyl-7-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(29) 4-[(1-ethyl-5-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole, hydrochloride,
(30) 4-[(6-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(31) 4-[(5-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(32) 4-[(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(33) 4-[(7-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(34) 4-[(5-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(35) 4-[(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(36) 4-[(5-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole hydrochloride,
(37) 4-[(7-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(38) 4-[(5-ethoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(39) 4-[(6-ethoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(40) 4-[(7-ethoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(41) 4-[(1-methyl-6-propoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(42) 4-[(1-methyl-6-isobutoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole.
The compounds of the present invention include, in addition to the abovementioned compounds, stereoisomers, and acid or base salts of these compounds. Examples of acids to form acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, and glutamic acid. Examples of bases to form base salts include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, organic bases such as lower alkyl amines, lower alcohol amines, basic amino acids such as lysine, arginine, and ornithine, and ammonium. Furthermore, hydrates and solvates with lower alcohols and other solvents may also be formed.
The compounds of the present invention can be produced by the following method. Briefly, a 1-tetralone compound with a hydrogen or alkoxyl group is heated with pyridylcarbaldehyde which has a 3- or 4-pyridyl group, or 1H-imidazole-4-carbaldehyde under acidic conditions. The resulting substituted 1-tetralone is reduced using an appropriate reducing agent, and the reduced compound is then treated with an appropriate Grignard reagent or reduced with hydride, followed by dehydration to obtain the target compound of the present invention, i.e., a dihydronaphthalene compound. Further, a dihydronaphthalene compound having a hydroxyl group can be obtained by purification with, for example, boron tribromide. The reactions above are shown in the following scheme: 
The compounds of the present invention can be safely administered orally or parenterally as pharmaceutical preparations to humans and other animals. Methods of parenteral administration include intravenous injection, intramuscular injection, cutaneous injection, intraperitoneal injection, transdermal administration, transpulmonary administration, nasal administration, transenteral administration, intraoral administration, and transmucous administration. Examples of parenteral preparations include injectables, suppositories, aerosols and percutaneous absorbing tapes. Examples of preparations for oral administration include tablets (including sugar coated tablets, coated tablets and buccal tablets), dispersible powders, capsules (including soft capsules), granules (including coated granules), pills, troches, liquids, and pharmaceutically acceptable slow-releasing forms of the above. Examples of liquid compositions for oral administration include suspensions, emulsions, syrups (including dry syrups), and elixirs.
These preparations are produced as medicinal compositions together with pharmacologically acceptable carriers, excipients, disintegrating agents, lubricants, coloring agents, or the like according to known pharmaceutical production methods. Examples of carriers or excipients to be used for these preparations include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, and gentiana powder. Examples of binding agents include starch, gum tragacanth, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, ethylcellulose, and carboxymethylcellulose. Examples of disintegrating agents include starch, agar, gelatin powder, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, and sodium alginate. Examples of lubricating agents include magnesium stearate, talc, hydrogenated vegetable oils, and macrogol. Pharmaceutically acceptable coloring agents can be used.
Tablets and granules may be coated, if necessary, with sucrose, gelatin, hydroxypropylcellulose, purified shellac, gelatin, glycerine, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methyl methacrylate, methacrylic acid polymers, or the like, or with a layer of combination of two or more of these coating materials. Capsules made of ethylcellulose, gelatin or the like can also be used. Injectable agents can be prepared, if necessary, by adding pH controlling agents, buffering agents, stabilizers, solubilizing agents, or the like, according to the customary method.
The dosage of the compound of the present invention is not particularly restricted and would vary as a function of the severity of the condition to be treated, the age, health, and body weight of the patient, and other factors. A proposed dosage of 1-1000 mg, preferably 50-200 mg, per day for adult may be administered orally or parenterally once or several times a day.